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Chronic shoulder and upper extremity dysfunction are common in breast cancer survivors following surgery and adjuvant radiation therapy (RT) and can significantly affect quality of life. We hypothesize that radiation dose to key skeletal muscles located within the radiation field may impact patient-reported shoulder function in breast cancer survivors at least 1 year following the completion of post-lumpectomy RT. A total of 24 women in a single institution participated in this study. All received whole breast RT +/- lumpectomy cavity boost. Key skeletal muscles were retrospectively contoured on each individual's simulation computed tomography scan. Dose volume histograms were constructed to determine mean dose and V10-V40 for each muscle, with prescription dose converted to dose equivalent of 2 Gy (EQD2), assuming an alpha/beta ratio of 2.5 Gy. The Penn Shoulder Score (PSS) was calculated to capture patient-reported shoulder function. Spearman correlation analyses were used to examine associations between dose parameters and PSS. One-way ANOVAs were utilized to determine differences in radiation dose received in skeletal muscles and PSS by cancer quadrant, boost treatment, and boost location. The pectoralis minor (PMin) had significantly greater mean radiation dose and V10-V40 values than both the pectoralis major (PMaj) and the serratus anterior (SA) (P < 0.001), and the PMaj had a significantly greater mean radiation dose and V10 – V40 values than the SA (P < 0.001). Those who received boosts in upper quadrants had significantly greater mean radiation dose to the PMin than when boosts were in the central or lower quadrants (P < 0.001). Those who had a boost in the outer breast quadrants had higher V40 PMin values than those who had a boost in the inner breast quadrants (P = 0.011). Patients with central breast tumors reported lower PSS function scores than those with upper or lower quadrant tumors (P = 0.045), but inner/outer breast quadrant location did not significantly affect PSS scores (P > 0.05). No statistically significant correlations were found between radiation dose parameters (total radiation dose or V10-V40 values) and PSS values. The PMaj, PMin, and SA all receive a high radiation dose during post lumpectomy adjuvant RT, with the PMin demonstrating the highest mean dose and the highest percent of muscle exposed to at least 10 Gy – 40 Gy of radiation. Boost location also affected PMin mean dose. No significant correlations were found between radiation dose parameters and PSS in this small study cohort. Further investigation is warranted to quantify the radiation dose to key shoulder muscles in order to identify breast cancer survivors at a high risk of developing shoulder dysfunction. [ABSTRACT FROM AUTHOR]

Galvos smegenųtrauma (GST) yra vienas dažniausių neurologiniųsutrikimų. Iš visųGST 90 % yra lengvos, jųdažnis siekia 100-300/100 000 kasmet. Intrakranijinės lengvos galvos smegenųtraumos (LGST) komplikacijos nėra dažnos (10 %). Labai retai prireikia neurochirurginės intervencijos (1 %), tačiau tai gali būti pavojinga gyvybei (mirtingumas -0,1 %). Taigi, tikroji gydymo problema kyla dėl poreikio išsiaiškinti nedidelę gyvybei grėsmingos komplikacijos galimybę dideliam pacientųskaičiui. 2002 m. EFNS nuorodose taikytas geriausio ąrodymo požiūris, remiantis literatūra iki 2001 m. nurodant pradiną gydymą, KT indikacijas, hospitalizavimą ir pacientų, patyrusių LGST, stebėjimą. šios atnaujintos EFNS nuorodos siūlo selektyvesnę KT atlikimo taktiką, esant didiesiems (pavojingas traumos mechanizmas, GKS < 15 balų, GKS vertės sumažėjimas 2 balais, klinikiniai kaukolės (pamato) l ūžio požymiai, vėmimas, gydymas antikoaguliantais, potrauminiai traukuliai) ar mažiesiems (amžius, sąmonės netekimas, išliekanti anterogradinė amnezija, židininiai simptomai, galvos sumušimas, GKS balųblogėjimas) rizikos veiksniams. Nuorodos paremtos publikuotais sprendimais, esant aukštam ąrodymųlygiui. Be to, dabar egzistuoja rekomendacijos dėl KT atlikimo vaikams. Nors ir su žemesniu ąrodymųlygiu, pateikiamos nuorodos dėl klinikinio stebėjimo ligoninėje, siekiant išvengti galimųpavojingųkomplikacijų, ąskaitant elgesio sutrikimus (amnezija, sumišimas ir neramumas) ir infekciją. [ABSTRACT FROM AUTHOR]

Glioblastoma (GB) is a primary brain tumor that is lethal and challenging to treat. The 3-year overall survival (OS) of patients with this diagnosis has stayed the same since 2005. The patient is a 75-year-old woman who presented with progressive aphasia and was diagnosed with GB (WHO grade 4, IDH1/IDH2 wild type, ATRX intact, p53 and PTEN mutant, BRAF non-mutated, O 6 -methylguanine-DNA methyltransferase promoter methylated) and who underwent surgical resection, hypofractionated radiotherapy (HFRT) using intensity-modulated radiotherapy (IMRT) (4,005 cGy in 15 fractions) alone, and adjuvant temozolomide (TMZ). She was progression-free for approximately 20 months. Although planned, concurrent TMZ was not used during the complete first course of HFRT due to the patient's performance status. After recurrence, another HFRT (35 Gy in 10 fractions) was employed. She was progression-free on imaging for 8 months until a recent follow-up scan showed potential progression versus radiation-related change. At the time of this case report, her care is still ongoing. This represents a rare case of a long-term survivor of GB who has received two courses of HFRT, a treatment option that is usually used in those with predicted shorter survival times., Competing Interests: LS receives research support from GT Medical Technologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Mrvoljak, Mishra, Chen, Neil, Ehler, Terezakis and Sloan.)

In recent years, numerous evidence has been accumulated about the extent of A-to-I editing in human RNAs and the key role ADAR1 plays in the cellular editing machinery. It has been shown that A-to-I editing occurrence and frequency are tissue-specific and essential for some tissue development, such as the liver. To study the effect of ADAR1 function in hepatocytes, we have created Huh7.5 ADAR1 KO cell lines. Upon IFN treatment, the Huh7.5 ADAR1 KO cells show rapid arrest of growth and translation, from which they do not recover. We analyzed translatome changes by using a method based on sequencing of separate polysome profile RNA fractions. We found significant changes in the transcriptome and translatome of the Huh7.5 ADAR1 KO cells. The most prominent changes include negatively affected transcription by RNA polymerase III and the deregulation of snoRNA and Y RNA levels. Furthermore, we observed that ADAR1 KO polysomes are enriched in mRNAs coding for proteins pivotal in a wide range of biological processes such as RNA localization and RNA processing, whereas the unbound fraction is enriched mainly in mRNAs coding for ribosomal proteins and translational factors. This indicates that ADAR1 plays a more relevant role in small RNA metabolism and ribosome biogenesis., (© 2024 Roučová et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Introduction: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain., Methods: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified., Results: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations., Conclusions: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition., Clinical Trial Registration: NCT03749642., (© 2024. The Author(s).)

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD)., Methods: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses., Results: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%)., Discussion: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD., Trial Registration Information: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24)., Classification of Evidence: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

Colloid cyst of the third ventricle (CC) represents approximately 1% of intracranial tumours and 20% of intraventricular tumours. CC usually occurs between 20 and 50 years of age. During the first decade of life, it is diagnosed very rarely (1-2%). It can be most commonly found in the anterior part of the third ventricle at the foramen of Monro (1). It is often visualised during the computed tomography (CT) examination as a hyperdense focal lesion, it has variable change of the signal during magnetic resonance imaging (MRI) (2). CC has a benign character, however, a strategic position which may lead to acute hydrocephalus, intracranial hypertension syndrome, consciousness disorder, and even sudden death. This peracute hydrocephalus is an indication to an acute neurosurgical procedure (3).

Myosin binding protein-C (MyBP-C) is a multidomain protein that regulates muscle contraction. Mutations in MYBPC3, the gene encoding for the cardiac variant (henceforth called cMyBP-C), are amongst the most frequent causes of hypertrophic cardiomyopathy. Most mutations lead to a truncated version of cMyBP-C, which is most likely unstable. However, missense mutations have also been reported, which tend to cluster in the central domains of the cMyBP-C molecule. This suggests that these central domains are more than just a passive spacer between the better characterized N- and C-terminal domains. Here, we investigated the potential impact of four different missense mutations, E542Q, G596R, N755K, and R820Q, which are spread over the domains C3 to C6, on the function of MyBP-C on both the isolated protein level and in cardiomyocytes in vitro. Effect on domain stability, interaction with thin filaments, binding to myosin, and subcellular localization behavior were assessed. Our studies show that these missense mutations result in slightly different phenotypes at the molecular level, which are mutation specific. The expected functional readout of each mutation provides a valid explanation for why cMyBP-C fails to work as a brake in the regulation of muscle contraction, which eventually results in a hypertrophic cardiomyopathy phenotype. We conclude that missense mutations in cMyBP-C must be evaluated in context of their domain localization, their effect on interaction with thin filaments and myosin, and their effect on protein stability to explain how they lead to disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We present a patient-specific model to estimate tumor location in the thorax during radiation therapy using chest surface displacement as the surrogate signal., Methods: Two types of data are used for model construction: Four-dimensional computed tomography (4D-CT) images of the patient and the displacement of two points on the patient's skin on the thoracic area. Principal component analysis is used to fit the correspondence model. This model incorporates the recorded surrogate signals during radiation delivery as input and delivers the 3D trajectory of the tumor as output. We evaluated the accuracy of the proposed model on a respiratory phantom and five lung cancer patients., Results: For the respiratory phantom, the location of the center of the sphere during treatment was calculated in three directions: Left-Right (LR), Anterior-Posterior (AP) and, Superior-Inferior (SI). The error of localization was less than 1 mm in the LR and AP directions and less than 2 mm in the SI direction. The location of the tumor center for two of the patients, and the location of the apex of the diaphragm for the other three, was calculated in three directions. For all patients, the localization error in the LR and AP directions was less than 1.1 mm for two fractions and the maximum localization error in the SI direction was 6.4 mm., Conclusions: This work presents a feasibility study of utilizing surface displacement data to locate the tumor in the thorax during radiation treatment. Future work will validate the model on a larger patient population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

In adverse pregnancy a perturbed redox environment is associated with abnormal early-life cardiovascular development and function. Previous studies have noted alterations in the expression and/or activity of Nuclear Factor E2 Related Factor 2 (NRF2) and its antioxidant targets during human gestational diabetic (GDM) pregnancy, however to our knowledge the functional role of NRF2 in fetal 'priming' of cardiovascular dysfunction in obese and GDM pregnancy has not been investigated. Using a murine model of obesity-induced glucose dysregulated pregnancy, we demonstrate that NRF2 activation by maternal sulforaphane (SFN) supplementation normalizes NRF2-linked NQO1, GCL and CuZnSOD expression in maternal and fetal liver placental and fetal heart tissue by gestational day 17.5. Activation of NRF2 in utero in wild type but not NRF2 deficient mice improved markers of placental efficiency and partially restored fetal growth. SFN supplementation was associated with reduced markers of fetal cardiac oxidative stress, including Nox2 and 3-nitrotyrosine, as well as attenuation of cardiac mass and cardiomyocyte area in male offspring by postnatal day 52 and improved vascular function in male and female offspring by postnatal day 98. Our findings are the first to highlight the functional consequences of NRF2 modulation in utero on early-life cardiovascular function in offspring, demonstrating that activation of NRF2 affords cardiovascular protection in offspring of pregnancies affected by redox dysregulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

The demographic history of East-Central Europe after the Neolithic period remains poorly explored, despite this region being on the confluence of various ecological zones and cultural entities. Here, the descendants of societies associated with steppe pastoralists form Early Bronze Age were followed by Middle Bronze Age populations displaying unique characteristics. Particularly, the predominance of collective burials, the scale of which, was previously seen only in the Neolithic. The extent to which this re-emergence of older traditions is a result of genetic shift or social changes in the MBA is a subject of debate. Here by analysing 91 newly generated genomes from Bronze Age individuals from present Poland and Ukraine, we discovered that Middle Bronze Age populations were formed by an additional admixture event involving a population with relatively high proportions of genetic component associated with European hunter-gatherers and that their social structure was based on, primarily patrilocal, multigenerational kin-groups., (© 2023. The Author(s).)

Cardiomyocytes that are derived from human-induced pluripotent stem cells (iPSC-CM) are an exciting tool to investigate cardiomyopathy disease mechanisms at the cellular level as well as to screen for potential side effects of novel drugs. However, currently their benefit is limited due to their fairly immature differentiation status under conventional culture conditions. This review is mainly aimed at researchers outside of the iPSC-CM field and will describe potential pitfalls and which features at the level of the myofibrils would be desired to make them a more representative model system. We will also discuss different strategies that may help to achieve these., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2023.)

Decreased left ventricle (LV) function caused by genetic mutations or injury often leads to debilitating and fatal cardiovascular disease. LV cardiomyocytes are, therefore, a potentially valuable therapeutical target. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are neither homogeneous nor functionally mature, which reduces their utility. Here, we exploit cardiac development knowledge to instruct differentiation of hPSCs specifically toward LV cardiomyocytes. Correct mesoderm patterning and retinoic acid pathway blocking are essential to generate near-homogenous LV-specific hPSC-CMs (hPSC-LV-CMs). These cells transit via first heart field progenitors and display typical ventricular action potentials. Importantly, hPSC-LV-CMs exhibit increased metabolism, reduced proliferation, and improved cytoarchitecture and functional maturity compared with age-matched cardiomyocytes generated using the standard WNT-ON/WNT-OFF protocol. Similarly, engineered heart tissues made from hPSC-LV-CMs are better organized, produce higher force, and beat more slowly but can be paced to physiological levels. Together, we show that functionally matured hPSC-LV-CMs can be obtained rapidly without exposure to current maturation regimes., Competing Interests: N.A.-G. is the vice president of research and development at AnaBios, San Diego. P.E.M. is a founding partner and the chief corporate development officer of AnaBios, San Diego. The Francis Crick Institute has filed a patent application related to this work (WO 2020/245612), and A.S.B. is listed as an inventor. The Francis Crick Institute has granted an exclusive license to Axol Bioscience to commercialize the protocol for the generation and sale of cardiomyocytes for R&D and the provision of contract research services. N.D., C.B., J.C.S., and A.S.B. may benefit from this license., (Crown Copyright © 2023.)

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated regulatory protein frequently found mutated in patients suffering from hypertrophic cardiomyopathy (HCM). Recent in vitro experiments have highlighted the functional significance of its N-terminal region (NcMyBP-C) for heart muscle contraction, reporting regulatory interactions with both thick and thin filaments. To better understand the interactions of cMyBP-C in its native sarcomere environment, in situ Foerster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM) assays were developed to determine the spatial relationship between the NcMyBP-C and the thick and thin filaments in isolated neonatal rat cardiomyocytes (NRCs). In vitro studies showed that ligation of genetically encoded fluorophores to NcMyBP-C had no or little effect on its binding to thick and thin filament proteins. Using this assay, FRET between mTFP conjugated to NcMyBP-C and Phalloidin-iFluor 514 labeling the actin filaments in NRCs was detected by time-domain FLIM. The measured FRET efficiencies were intermediate between those observed when the donor was attached to the cardiac myosin regulatory light chain in the thick filaments and troponin T in the thin filaments. These results are consistent with the coexistence of multiple conformations of cMyBP-C, some with their N-terminal domains binding to the thin filament and others binding to the thick filament, supporting the hypothesis that the dynamic interchange between these conformations mediates interfilament signaling in the regulation of contractility. Moreover, stimulation of NRCs with β-adrenergic agonists reduces FRET between NcMyBP-C and actin-bound Phalloidin, suggesting that cMyBP-C phosphorylation reduces its interaction with the thin filament.

Pathogenic variants in ACTN2 , coding for alpha-actinin 2, are known to be rare causes of Hypertrophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocardiography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell-cycle defects and mitochondrial dysfunction. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteasomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteasomal system is activated; a mechanism that has been implicated in cardiomyopathies previously. In parallel, a lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell-cycle defects, the likely cause of the death of the embryos. The defects also have wide-ranging morphological consequences.

Four-and-a-half LIM domains protein 2 (FHL2) is an anti-hypertrophic adaptor protein that regulates cardiac myocyte signalling and function. Herein, we identified cardiomyopathy-associated 5 (CMYA5) as a novel FHL2 interaction partner in cardiac myocytes. In vitro pull-down assays demonstrated interaction between FHL2 and the N- and C-terminal regions of CMYA5. The interaction was verified in adult cardiac myocytes by proximity ligation assays. Immunofluorescence and confocal microscopy demonstrated co-localisation in the same subcellular compartment. The binding interface between FHL2 and CMYA5 was mapped by peptide arrays. Exposure of neonatal rat ventricular myocytes to a CMYA5 peptide covering one of the FHL2 interaction sites led to an increase in cell area at baseline, but a blunted response to chronic phenylephrine treatment. In contrast to wild-type hearts, loss or reduced FHL2 expression in Fhl2-targeted knockout mouse hearts or in a humanised mouse model of hypertrophic cardiomyopathy led to redistribution of CMYA5 into the perinuclear and intercalated disc region. Taken together, our results indicate a direct interaction of the two adaptor proteins FHL2 and CMYA5 in cardiac myocytes, which might impact subcellular compartmentation of CMYA5., (© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objectives: Elevated blood glucose and CRP (C-reactive protein) are usually related to a worsened clinical outcome in neurological diseases. This association in Guillain-Barré syndrome (GBS) has been studied rarely. We tried to analyse if hyperglycaemia and CRP at admission may influence the outcome of GBS, including mechanically ventilated (MV) patients., Methods: We retrospectively studied 66 patients (40 males, 19-93 years, average 56 years) without diabetes mellitus and free of corticoid treatment, who fulfilled the clinical criteria for diagnosis of GBS. Hyperglycaemia (the level of fasting plasma glucose, FPG) was defined as blood glucose level >5.59 mmol/L according to our laboratory. CRP >5 mg/L was considered as an abnormally elevated value., Results: At admission, 32 GBS patients (48%) had hyperglycaemia according to FPG level. A severe form of GBS (>4 according to Hughes GBS scale) was observed in 17 patients (26%); and 8 of them (47%) had hyperglycaemia. Fourteen patients (21%) were MV, and in 10 of them (71%) hyperglycaemia was present. CRP was significantly increased in MV patients. The linear model revealed a significant relationship between CRP and glycemia ( p = 0.007) in subjects without MV ( p = 0.049). In subjects with MV the relationship was not significant ( p = 0.2162, NS)., Conclusion: In the acute phase of GBS at admission, hyperglycaemia and higher CRP occur relatively frequently, and may be a risk factor for the severity of GBS. Stress hyperglycaemia due to impaired glucose homeostasis could be one explanation for this condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Štětkářová, Ehler, Židó, Lauer, Polák, Keller and Peisker.)

The need for acquiring at least three images to reconstruct an optical section of a sample limits the acquisition rate in structured illumination microscopy (SIM) for optical sectioning. In polarized illumination coded structured illumination microscopy (picoSIM) the three individual light patterns are encoded in a single polarized illumination light distribution, enabling the acquisition of the complete SIM data in a single exposure. Here, we describe our experimental set-up and show experimental results acquired with sequential and single-shot picoSIM. This article is part of the Theo Murphy meeting issue 'Super-resolution structured illumination microscopy (part 2)'.

Background: Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited., Methods: This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing)., Results: The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p < 0.001). Multiple regression analysis demonstrated the severity of pain and neuropathy, catastrophic thinking, type 2 DM, lower age and female sex as independent contributors to depression and anxiety., Conclusions: In addition to the severity of neuropathic pain and its cognitive processing, the severity of diabetic polyneuropathy and demographic factors are key independent contributors to emotional distress in diabetic individuals., Significance: In large cohorts of well-defined painless and painful diabetic polyneuropathy patients and diabetic subjects without polyneuropathy, we found a high prevalence of the symptoms of depression and anxiety, mainly in painful individuals. We have confirmed neuropathic pain, its severity and cognitive processing (pain catastrophizing) as dominant risk factors for depression and anxiety. Furthermore, some demographic factors (lower age, female sex), type 2 diabetes mellitus and severity of diabetic polyneuropathy were newly identified as important contributors to emotional distress independent of pain., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Objective: We aim to identify maternal genetic affinities between the Middle to Final Neolithic (3850-2300 BC) populations from present-day Poland and possible genetic influences from the Pontic steppe., Materials and Methods: We conducted ancient DNA studies from populations associated with Złota, Globular Amphora, Funnel Beaker, and Corded Ware cultures (CWC). We sequenced genomic libraries on Illumina platform to generate 86 complete ancient mitochondrial genomes. Some of the samples were enriched for mitochondrial DNA using hybridization capture., Results: The maternal genetic composition found in Złota-associated individuals resembled that found in people associated with the Globular Amphora culture which indicates that both groups likely originated from the same maternal genetic background. Further, these two groups were closely related to the Funnel Beaker culture-associated population. None of these groups shared a close affinity to CWC-associated people. Haplogroup U4 was present only in the CWC group and absent in Złota group, Globular Amphora, and Funnel Beaker cultures., Discussion: The prevalence of mitochondrial haplogroups of Neolithic farmer origin identified in Early, Middle and Late Neolithic populations suggests a genetic continuity of these maternal lineages in the studied area. Although overlapping in time - and to some extent - in cultural expressions, none of the studied groups (Złota, Globular Amphora, Funnel Beaker), shared a close genetic affinity to CWC-associated people, indicating a larger extent of cultural influence from the Pontic steppe than genetic exchange. The higher frequency of haplogroup U5b found in populations associated with Funnel Beaker, Globular Amphora, and Złota cultures suggest a gradual maternal genetic influx from Mesolithic hunter-gatherers. Moreover, presence of haplogroup U4 in Corded Ware groups is most likely associated with the migrations from the Pontic steppe at the end of the Neolithic and supports the observed genetic distances., (© 2021 Wiley Periodicals LLC.)

Muscle specific signaling has been shown to originate from myofilaments and their associated cellular structures, including the sarcomeres, costameres or the cardiac intercalated disc. Two signaling hubs that play important biomechanical roles for cardiac and/or skeletal muscle physiology are the N2B and N2A regions in the giant protein titin. Prominent proteins associated with these regions in titin are chaperones Hsp90 and αB-crystallin, members of the four-and-a-half LIM (FHL) and muscle ankyrin repeat protein (Ankrd) families, as well as thin filament-associated proteins, such as myopalladin. This review highlights biological roles and properties of the titin N2B and N2A regions in health and disease. Special emphasis is placed on functions of Ankrd and FHL proteins as mechanosensors that modulate muscle-specific signaling and muscle growth. This region of the sarcomere also emerged as a hotspot for the modulation of passive muscle mechanics through altered titin phosphorylation and splicing, as well as tethering mechanisms that link titin to the thin filament system., Competing Interests: Conflict of interestFarah Sheikh is a cofounder of Papillon Therapeutics Inc. All other co-authors (R.v.d.P., A.D., C.O., E.E. and S.L.) declare that they have no conflicts of interest., (© The Author(s) 2021.)

Titin truncating variants are a well-established cause of cardiomyopathy; however, the role of titin missense variants is less well understood. Here we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported titin A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Heterozygous and homozygous mice carrying the titin A178D missense variant were characterised in vivo by echocardiography. Heterozygous mice had no detectable phenotype at any time point investigated (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the foetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified downregulation of telethonin and four-and-a-half LIM domain 2, as well as the upregulation of heat shock proteins and myeloid leukaemia factor 1. Loss of telethonin from the cardiac Z-disc was accompanied by proteasomal degradation; however, unfolded telethonin accumulated in the cytoplasm, leading to a proteo-toxic response in the mice.We show that the titin A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism: because the titin A178D variant abolishes binding of telethonin, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of telethonin by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by gradual loss of upper and lower motor neurons and their pathways, usually without affecting the extraocular and sphincter muscles. The cause of the disease is not yet known. It is a chain of subsequent events, ending in programmed cell death in selective neuronal subpopulations. The prognosis for survival is rather short with a median of 2 to 4 years. Survival may be prolonged based on prompt diagnosis, ALS subtype and proper management with supportive treatment (tracheostomy, gastrostomy, etc.). According to the clinical picture, the typical form of ALS with upper and lower motoneuron involvement and progressive bulbar paralysis with bulbar muscle involvement is observed. The ALS form with progressive muscle atrophy, where only the lower motoneuron is affected, and primary lateral sclerosis with only upper motoneuron damage are rare. Familiar forms of ALS (FALS) associated with specific genes (the most common is C9orf72) have been discovered. FALS is usually associated with dementia (frontotemporal lobar dementia, FTLD), behavioral disorders, cognitive dysfunction and impairment of executive functions. The diagnosis of ALS is determined by excluding other conditions and utilizing clinical examinations, laboratory and genetic tests and nerve conduction/needle electromyography studies (EMG). Needle EMG records abnormal activities at rest and looks for neurogenic patterns during muscle contraction. Motor evoked potentials after transcranial magnetic stimulation remain the test of choice to identify impairment of upper motor neurons. New biochemical, neurophysiological and morphological biomarkers are extensively studied as early diagnostic and prognostic factors and have implications for clinical trials, research and drug development.

Aim of the Study: Spontaneous spinal epidural haematomas (SSEH) are rare nosological units wherein acute collections of blood develop in the spinal canal. SSEH are usually manifested by sudden severe back pain accompanied by the development of neurological symptoms. In this study, we retrospectively describe management and the main risk factors of SSEH in a series of 14 cases., Material and Methods: Between 2010 and 2019, we examined 14 patients (age range 17-89 years, 10 women) diagnosed with SSEH. Eight cases were patients using anticoagulant therapies (six warfarin, one dabigatran, one apixaban) and two others were using ASA of 100 mg/day. The exact localisation and extent of changes was determined from acute magnetic resonance imaging. Three people using warfarin had INR values higher than 3.0 at the time of their diagnosis., Results: Ten patients (71%) were taking oral anticoagulants or antiplatelet agents. In seven patients, SSEH were localised in the lower cervical/thoracic spine. Ten patients (71%) had arterial hypertension. Six patients underwent acute surgery due to rapidly developing spinal cord compression. Eight patients (57%) with slight or mild neurological symptoms were successfully managed without surgery., Conclusions: SSEH should be suspected in any patient receiving anticoagulant/antiplatelet agents who complains of sudden, severe back pain accompanied by neurological symptoms. SSEH is mostly localised in the lower cervical/thoracic spine. Arterial hypertension appears to be a risk factor of SSEH. Early decompression is an important therapeutic approach; in cases with minor neurological deficits, conservative treatment may be chosen.

A number of neurological complications have been reported after the administration of flu vaccine, including Guillain-Barré syndrome (GBS), especially after vaccination against swine flu. Only facial nerve neuropathy has thus far been reported after vaccination against COVID-19. More recently, there was a case of an elderly woman with GBS. In our report, we describe a case of a 42-year-old, previously almost healthy male who developed sensory symptoms 14 days after the first dose of Pfizer vaccine. One week later, the patient developed right facial nerve palsy and lower limb weakness and was no longer able to walk. Albuminocytological dissociation was detected in the cerebrospinal fluid, and there were inflammatory radicular changes in MRI scans of the lumbosacral spine. EMG indicated significant demyelinating polyradiculoneuritis and no antibodies against gangliosides were demonstrated. A 5-day course of immunoglobulins at a dose of 2 g/kg lead to a significant improvement and the patient was soon able to walk. In conclusion, we report a case of Guillan-Barré syndrome after COVID-19 vaccine in a young patient with a rapid diagnosis and prompt administration of immunoglobulins.

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) resemble fetal cardiomyocytes and electrical stimulation (ES) has been explored to mature the differentiated cells. Here, we hypothesize that ES applied at the beginning of the differentiation process, triggers both differentiation of the hiPSC-CMs into a specialized conduction system (CS) phenotype and cell maturation. We applied ES for 15 days starting on day 0 of the differentiation process and found an increased expression of transcription factors and proteins associated with the development and function of CS including Irx3, Nkx2.5 and contactin 2, Hcn4 and Scn5a, respectively. We also found activation of intercalated disc proteins (Nrap and β-catenin). We detected ES-induced CM maturation as indicated by increased Tnni1 and Tnni3 expression. Confocal micrographs showed a shift towards expression of the gap junction protein connexin 40 in ES hiPSC-CM compared to the more dominant expression of connexin 43 in controls. Finally, analysis of functional parameters revealed that ES hiPSC-CMs exhibited faster action potential (AP) depolarization, longer intracellular Ca 2+ transients, and slower AP duration at 90% of repolarization, resembling fast conducting fibers. Altogether, we provided evidence that ES during the differentiation of hiPSC to cardiomyocytes lead to development of cardiac conduction-like cells with more mature cytoarchitecture. Thus, hiPSC-CMs exposed to ES during differentiation can be instrumental to develop CS cells for cardiac disease modelling, screening individual drugs on a precison medicine type platform and support the development of novel therapeutics for arrhythmias., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The contraction and relaxation of the heart is controlled by stimulation of the β1-adrenoreceptor (AR) signaling cascade, which leads to activation of cAMP-dependent protein kinase (PKA) and subsequent cardiac protein phosphorylation. Phosphorylation is counteracted by the main cardiac protein phosphatases, PP2A and PP1. Both kinase and phosphatases are sensitive to intramolecular disulfide formation in their catalytic subunits that inhibits their activity. Additionally, intermolecular disulfide formation between PKA type I regulatory subunits (PKA-RI) has been described to enhance PKA's affinity for protein kinase A anchoring proteins, which alters its subcellular distribution. Nitroxyl donors have been shown to affect contractility and relaxation, but the mechanistic basis for this effect is unclear. The present study investigates the impact of several nitroxyl donors and the thiol-oxidizing agent diamide on cardiac myocyte protein phosphorylation and oxidation. Although all tested compounds equally induced intermolecular disulfide formation in PKA-RI, only 1-nitrosocyclohexalycetate (NCA) and diamide induced reproducible protein phosphorylation. Phosphorylation occurred independently of β 1 -AR activation, but was abolished after pharmacological PKA inhibition and thus potentially attributable to increased PKA activity. NCA treatment of cardiac myocytes induced translocation of PKA and phosphatases to the myofilament compartment as shown by fractionation, immunofluorescence, and proximity ligation assays. Assessment of kinase and phosphatase activity within the myofilament fraction of cardiac myocytes after exposure to NCA revealed activation of PKA and inhibition of phosphatase activity thus explaining the increase in phosphorylation. The data suggest that the NCA-mediated effect on cardiac myocyte protein phosphorylation orchestrates alterations in the kinase/phosphatase balance., Competing Interests: Conflict of interest—The authors declare that they have no conflict of interest with the content of this article., (© 2020 Diering et al.)

Background: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy., Objective: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy., Methods: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety., Results: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were - 3.1, - 2.6, and - 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval - 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval - 1.54, - 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders., Conclusions: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ., Clinical Trial Registration: NCT03202979, date of registration: 29/06/2017.

Purpose/objectives: Three-dimensional (3D) printing is recognized as an effective clinical and educational tool in procedurally intensive specialties. However, it has a nascent role in radiation oncology. The goal of this investigation is to clarify the extent to which 3D printing applications are currently being used in radiation oncology through a systematic review of the literature., Materials/methods: A search protocol was defined according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Included articles were evaluated using parameters of interest including: year and country of publication, experimental design, sample size for clinical studies, radiation oncology topic, reported outcomes, and implementation barriers or safety concerns., Results: One hundred and three publications from 2012 to 2019 met inclusion criteria. The most commonly described 3D printing applications included quality assurance phantoms (26%), brachytherapy applicators (20%), bolus (17%), preclinical animal irradiation (10%), compensators (7%), and immobilization devices (5%). Most studies were preclinical feasibility studies (63%), with few clinical investigations such as case reports or series (13%) or cohort studies (11%). The most common applications evaluated within clinical settings included brachytherapy applicators (44%) and bolus (28%). Sample sizes for clinical investigations were small (median 10, range 1-42). A minority of articles described basic or translational research (11%) and workflow or cost evaluation studies (3%). The number of articles increased over time (P < 0.0001). While outcomes were heterogeneous, most studies reported successful implementation of accurate and cost-effective 3D printing methods., Conclusions: Three-dimensional printing is rapidly growing in radiation oncology and has been implemented effectively in a diverse array of applications. Although the number of 3D printing publications has steadily risen, the majority of current reports are preclinical in nature and the few clinical studies that do exist report on small sample sizes. Further dissemination of ongoing investigations describing the clinical application of developed 3D printing technologies in larger cohorts is warranted., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Cardiomyocytes, the cells generating contractile force in the heart, are connected to each other through a highly specialised structure, the intercalated disc (ID), which ensures force transmission and transduction between neighbouring cells and allows the myocardium to function in synchrony. In addition, cardiomyocytes possess an intrinsic ability to sense mechanical changes and to regulate their own contractile output accordingly. To achieve this, some of the components responsible for force transmission have evolved to sense changes in tension and to trigger a biochemical response that results in molecular and cellular changes in cardiomyocytes. This becomes of particular importance in cardiomyopathies, where the heart is exposed to increased mechanical load and needs to adapt to sustain its contractile function. In this review, we will discuss key mechanosensing elements present at the intercalated disc and provide an overview of the signalling molecules involved in mediating the responses to changes in mechanical force.

Objective: In this work we aim to investigate the origins and genetic affinities of Bronze Age populations (2,400-1,100 BC) from the region of southern Poland and to trace maternal kinship patterns present in the burials of those populations by the use of complete mitochondrial genomes., Materials and Methods: We performed ancient DNA analyses for Bronze Age individuals from present-day Poland associated with the Strzyżow culture, the Mierzanowice culture, and the Trzciniec Cultural circle. To obtain complete mitochondrial genomes, we sequenced genomic libraries using Illumina platform. Additionally, hybridization capture was used to enrich some of the samples for mitochondrial DNA. AMS 14 C-dating was conducted for 51 individuals to verify chronological and cultural attribution of the analyzed samples., Results: Complete ancient mitochondrial genomes were generated for 80 of the Bronze Age individuals from present-day Poland. The results of the population genetic analyses indicate close maternal genetic affinity between Mierzanowice, Trzciniec, and Corded Ware culture-associated populations. This is in contrast to the genetically more distant Strzyżów people that displayed closer maternal genetic relation to steppe populations associated with the preceding Yamnaya culture and Catacomb culture, and with later Scythians. Potential maternal kinship relations were identified in burials of Mierzanowice and Trzciniec populations analyzed in this study., Discussion: Results revealed genetic continuity from the Late Neolithic Corded Ware groups to Bronze Age Mierzanowice and Trzciniec-associated populations, and possible additional genetic contribution from the steppe to the formation of the Strzyżów-associated group at the end of 3rd millennium BC. Mitochondrial patterns indicated several pairs of potentially maternally related individuals mostly in Trzciniec-associated group., (© 2020 Wiley Periodicals, Inc.)

Purpose: To characterize the dose distribution in water of a novel beta-emitting brachytherapy source for use in a Conformal Superficial Brachytherapy (CSBT) device., Methods and Materials: Yttrium-90 ( 90 Y) sources were designed for use with a uniquely designed CSBT device. Depth dose and planar dose measurements were performed for bare sources and sources housed within a 3D printed source holder. Monte Carlo simulated dose rate distributions were compared to film-based measurements. Gamma analysis was performed to compare simulated and measured dose rates from seven 90 Y sources placed simultaneously using the CSBT device., Results: The film-based maximum measured surface dose rate for a bare source in contact with the surface was 3.35 × 10 -7  cGy s -1  Bq -1 . When placed in the source holder, the maximum measured dose rate was 1.41 × 10 -7  cGy s -1  Bq -1 . The Monte Carlo simulated depth dose rates were within 10% or 0.02 cm of the measured dose rates for each depth of measurement. The maximum film surface dose rate measured using a seven-source configuration within the CSBT device was 1.78 × 10 -7  cGy s -1  Bq -1 . Measured and simulated dose rate distribution of the seven-source configuration were compared by gamma analysis and yielded a passing rate of 94.08%. The gamma criteria were 3% for dose-difference and 0.07056 cm for distance-to-agreement. The estimated measured dose rate uncertainty was 5.34%., Conclusions: 90 Y is a unique source that can be optimally designed for a customized CSBT device. The rapid dose falloff provided a high dose gradient, ideal for treatment of superficial lesions. The dose rate uncertainty of the 90 Y-based CSBT device was within acceptable brachytherapy standards and warrants further investigation., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

The sarcomere is the basic unit of the myofibrils, which mediate skeletal and cardiac Muscle contraction. Two transverse structures, the Z-disc and the M-band, anchor the thin (actin and associated proteins) and thick (myosin and associated proteins) filaments to the elastic filament system composed of titin. A plethora of proteins are known to be integral or associated proteins of the Z-disc and its structural and signalling role in muscle is better understood, while the molecular constituents of the M-band and its function are less well defined. Evidence discussed here suggests that the M-band is important for managing force imbalances during active muscle contraction. Its molecular composition is fine-tuned, especially as far as the structural linkers encoded by members of the myomesin family are concerned and depends on the specific mechanical characteristics of each particular muscle fibre type. Muscle activity signals from the M-band to the nucleus and affects transcription of sarcomeric genes, especially via serum response factor (SRF). Due to its important role as shock absorber in contracting muscle, the M-band is also more and more recognised as a contributor to muscle disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Acute compartment syndrome occurs most frequently in connection with injuries, terminal or chemical damage of tissues, ischemia, the activity of toxins or in patients with tissue ischemia or muscle necrosis. Clinical findings have found pronounced pain, followed by paresthesias, pallor, and paresis. Decreased pulsation of arteries has also been a frequent finding. In severe forms decompressive fasciotomy has been indicated within the first 12-24 hours after diagnosis. In the following paper, the authors present the case report of a 68-year woman who swallowed 1500 mg of trazodone as an attempt at suicide. After 12 hours her husband found her lying on the carpet with compression of the left arm under the trunk. The patient was treated conservatively and followed clinically, examined by ultrasonography, EMG and finally MRI.

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.